This proposal, entitled, Developmental mechanisms of leptin resistance, is an application for competitive renewal of DK57768-09. The long-term outlook of our previous and proposed studies under this award is to understand molecular and neural mechanisms that impair leptin action and promote obesity and metabolic dysfunction. During the current funding period, we focused upon the mechanisms by which LepRb regulates hypothalamic physiology and may mediate feedback inhibition. Major conclusions from this work include the roles for Tyr985 (along with other LepRb signals) in the attenuation of LepRb action. Multiple lines of evidence now support the notion that cellular processes that attenuate LepRb signaling contribute to obesity and leptin resistance in vivo. Additional neural/developmental mechanisms contribute to the inception of obesity, however. Importantly, altered perinatal nutrition initiates a program that promotes obesity and metabolic syndrome in adulthood. Lack of leptin action or alterations in nutrient availability during this crucial perinatal window disrupts the development of projections from ARC neurons to their target nuclei, suggesting a potential role for leptin and the development of this ARC circuit in early metabolic programming. Many issues regarding these alterations in ARC projections remain to be addressed, however. As these issues are difficult to address with standard tools, we have generated a number of novel transgenic systems that will enable us to probe these issues in this application. The requirement for diverse intellectual and technical expertise in this proposal dictates an intimate collaboration between the Myers and Simerly labs. Together, we will: (1) Define the functional consequences of leptin deficiency on the development of leptin-regulated neural circuitry. (2) Examine the programming of leptin-regulated neural circuitry by perinatal undernutrition. (3) Determine the mechanisms that underlie the leptin-mediated developmental programming of the ARC neural circuitry. These studies will define the neural consequences of altered leptin and perinatal nutritional status within a core component of the neural circuitry that regulates energy homeostasis, as well as defining the mechanisms underlying these processes. The mechanistic insights derived from these studies will define processes that likely contribute to the inception of metabolic disease. PUBLIC HEALTH RELEVANCE: Leptin is a key regulator of body energy homeostasis and metabolism, and impaired leptin action may contribute to a variety of metabolic diseases. Understanding the mechanisms that may interfere with leptin action to mediate obesity and metabolic dysfunction is thus crucial. We have thus been working to define the mechanisms by which the leptin receptor, LepRb, mediates feedback inhibition of leptin action and to define the contribution of these processes to obesity in vivo. While these processes can contribute to the regulation of adiposity, they explain the propagation rather than the onset of obesity. In contrast, perinatal metabolic programming clearly underlies important aspects of the inception of obesity. Developmental alteration of hypothalamic leptin-responsive circuits represents a likely mediator of this perinatal programming. We have thus generated a number of novel mouse genetic models with which to analyze the mechanisms and consequences of perinatal hypothalamic programming by leptin and altered nutrition.